Rocking the foundations of molecular

John S. Mattick Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia

n PNAS, Nelson et al. present in- carrying a null of Apobec1 had Interestingly, Apobec1 is an RNA- triguing evidence that challenges the a transgenerational influence on the phe- editing enzyme that is required for I fundamental tenets of genetics (1). notype of male F1, F2, and F3 descend- embryonic development, orthologues of It has long been assumed that the ants, compared with WT and male which, including the “activation-induced” inherited contribution to is ancestral controls, even though the allele cytidine deaminase, modulate cytidine embedded in DNA sequence variations was not present in F1, F2 or F3—an effect methylation following deamination to thy- in, and interactions between, the that can be reversed by backcrossing midine and presumptively mismatch repair endogenous to the organism, i.e., through the alternative germ lineage. (but which may involve more complex derived from parents with some degree of These findings add to a growing list of preprogrammed lineage- and/or context- fi – de novo variation. This assumption un- studies indicating that genetic influence of speci c mutation) (14 16). Moreover, ac- derlies most genetic analysis, including tivation-induced cytidine deaminase, the fleet of genome-wide association which is involved in somatic hyper- studies launched in recent years to identify Nelson et al. provide mutation and rearrangement of Ig genes, is genomic loci that influence complex hu- expressed in pluripotent cells (17), affects man traits and diseases. Not surprisingly, data suggesting that erasure of DNA methylation in mouse in contrast to mutations in protein-coding germ cells (18), and is required for re- sequences, which underlie high epigenetic inheritance programming toward pluripotency (15). monogenic disorders, the vast majority may be far more of the identified loci map to non–protein- Soma to Germline Inheritance coding intergenic and intronic regions, important and pervasive The available evidence not only suggests which comprise the vast majority of the an intimate interplay between genetic and genome. These regions contain the regu- than expected. epigenetic inheritance, but also that this latory information that controls interplay may involve communication be- expression and underlies most phenotypic tween the soma and the germline. This idea variation (2). ancestral variants can commonly reach contravenes the so-called Weismann bar- However, the perplexing and much de- through multiple generations and rival rier, sometimes referred to as Biology’s bated surprise has been that most genome- conventional inheritance in strength. Second Law, which is based on flimsy evi- wide association studies have superficially These include the demonstrations, with dence and a desire to distance Darwinian failed to locate more than a small per- considerable molecular and genetic detail, evolution from Lamarckian inheritance at centage of the inherited component of of epigenetic inheritance (i.e., “para- the time of the Modern Evolutionary complex traits. This may be a result of mutation”) in plants, and, although still Synthesis. However, the belief that the a number of possibilities that are not somewhat controversial, in animals (6). soma and germline do not communicate is — mutually exclusive (3, 4), including sys- Mechanistically, epigenetic memory is patently incorrect as demonstrated by the tematic underestimation of the fraction of embedded in DNA methylation and/or multigenerational inheritance of RNAi- the and epistatic interactions histone modifications, which are thought mediated delivered to somatic measured by common SNPs used to to be erased in germ cells, but may not be, cells in (8). Thus, if RNA editing can alter hard- monitor haplotype blocks, a larger than at least completely, as some chromatin wired genetic information in a context- expected contribution of rare recent structure appears to be preserved (7). variants that lie under the SNP typing dependent manner, and thereby alter Some information may also be cotrans- epigenetic memory, it is feasible that not radar, and intergenerational epigenetic mitted by RNA (7, 8). inheritance (5), which is not polled by only allelic but also environmental history DNA sequence. However, the latter has RNA Regulation of Epigenetic State may shape phenotype, and provide a far more plastic and dynamic inheritance not thus far been paid much attention or Indeed, there is now good evidence that given much credence as a major factor. platform than envisaged by the genetic epigenetic inheritance is RNA-mediated orthodoxy of the past century. Evidence of Intergenerational (9), or, perhaps more precisely, RNA- Epigenetic Inheritance directed, as it is becoming clear that RNA at the Center a major function of the large numbers of fi Now Nelson et al. (1) provide data sug- Moreover, the nding of extraordinarily gesting that epigenetic inheritance may be noncoding RNAs that are differentially dynamic noncoding transcription in far more important and pervasive than expressed from the genome (10) is to complex organisms suggests that the long- expected. Although the genetics are com- direct chromatin-modifying complexes to held idea that is primarily plex, Nelson et al. (1) show in an elegant their sites of action (11, 12). This conclu- controlled by combinatoric interactions fi and comprehensive series of analyses that sion is consistent with the recent ndings between cis-acting transcription factors grand-maternal (but not grand-paternal) of the ENCODE project, suggesting that and their cognate binding sites is also heterozygosis for a null allele of the Apo- much if not most of the human genome incorrect, but rather that RNA may be bec1 cytidine deaminase gene modulates may be functional (13), and explains the testicular germ cell tumor susceptibility informational basis of the extraordinary and embryonic viability in male (mouse) precision and complexity of the epigenetic Author contributions: J.S.M. wrote the paper. descendants that do not carry the null superstructure of the genome in different The authors declare no conflict of interest. allele, an effect that persists for at least cells required to specify developmental See companion article on pages E2766 and 16414. three generations. That is, female F0 mice architecture. 1E-mail: [email protected].

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the computational engine of the evolu- complex and cognitively advanced It is time to reassess many assumptions tion and ontogeny of developmentally organisms (19). in molecular biology and genetics.

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